Actas Dermosifiliogr.

2020;111(6):471---480

REVIEW

Recurrent Aphthous Stomatitis夽

J. Sánchez,a C. Conejero,b R. Conejeroc,∗

a
Servicio de Dermatología, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain
b
Unidad de Dermatología, Centro Médico Millenium, Zaragoza, Spain
c
Departamento de Dermatología, Hospital Royo Villanova, Zaragoza, Spain

Received 12 May 2019; accepted 25 September 2019

Available online 15 July 2020

KEYWORDS Abstract Recurrent aphthous stomatitis is a chronic inflammatory disease of the oral mucosa.
Recurrent aphthous It is characterized by painful mouth ulcers that cannot be explained by an underlying disease.
stomatitis; Recurrent oral mucosal ulcers require a proper differential diagnosis to rule out other possi-
Aphthae; ble causes before recurrent aphthous stomatitis is diagnosed. The condition is common, with
Oral ulcers; prevalence rates ranging from 5% to 60% in different series. Its pathogenesis is unknown, but
Periodic fever multiple factors are considered to play a part. There are no standardized treatments for this
syndrome condition and none of the treatments are curative. The goal of any treatment should be to
alleviate pain, reduce the duration of ulcers, and prevent recurrence.
© 2020 AEDV. Published by Elsevier España, S.L.U. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PALABRAS CLAVE Aftosis oral recidivante

Aftosis oral
recidivante; Resumen La aftosis oral recidivante es una enfermedad inflamatoria crónica de la mucosa
Afta; oral. Se caracteriza por presentar úlceras dolorosas en la cavidad oral sin que se encuentre una
Ulceras orales; enfermedad subyacente que lo justifique. Ante la aparición de úlceras recidivantes en la mucosa
Síndrome periódico; oral habrá que realizar un correcto diagnóstico diferencial y descartar otras causas antes de
Mucosa oral llegar al diagnóstico de aftosis oral recidivante. Se trata de una enfermedad frecuente, según
la población estudiada se han documentado prevalencias entre el 5 hasta el 60%. Su patogenia
es desconocida pero se considera multifactorial. El tratamiento no está estandarizado, y no hay
un tratamiento curativo, se pretende disminuir el dolor durante el brote, acortar la duración
del mismo y evitar la aparición de nuevas lesiones.
© 2020 AEDV. Publicado por Elsevier España, S.L.U. Este es un artı́culo Open Access bajo la
licencia CC BY-NC-ND (http://creativecommons.org/licenses/by-nc-nd/4.0/).

夽 Please cite this article as: Sánchez J, Conejero C, Conejero R. Aftosis oral recidivante. Actas Dermosifiliogr. 2020;111:471---480.
∗ Corresponding author.
E-mail addresses: raquel conejero@hotmail.com, rconejero@salud.aragon.es (R. Conejero).

1578-2190/© 2020 AEDV. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
472
Introduction
Recurrent aphthous stomatitis (RAS) is characterized by the
appearance of painful, round, well-defined ulcers with ery-
thematous borders and a grayish-yellow pseudomembranous
base in the oral cavity of otherwise healthy patients. A burn-
ing sensation may precede the appearance of the ulcers by
2 to 48 hours.1
Epidemiology
RAS is the most frequent cause of ulcers on the oral mucosa.
It affects 5% to 25% of the general population,2 although
prevalence may vary from 5% to 60%3 depending on the
study and on the population assessed, the diagnostic criteria
applied, and environmental factors.
The peak age for onset of RAS is between 10 and 19
years, and although the condition is less frequent in adults,
it may persist throughout a person’s life. No sex differences
in prevalence have been recorded.4
Pathogenesis
RAS belongs to the family of chronic inflammatory dis-
eases of the oral mucosa. Its etiology and pathogenesis are
unknown, although it is considered a multifactorial disease,
and various triggers have been reported (Fig. 1). In genet-
ically predisposed patients, the effect of specific factors
is thought to initiate a proinflammatory cytokine cascade
targeting specific areas of the oral mucosa.5
• Genetic factors: Heredity plays a key role in the devel-
opment of RAS. The probability of having RAS increases if
one or both parents have had the disease; in 24%-46% of
cases, patients have a family history.6,7 Moreover, patients
with a family history experience recurrences much more
often and have a more severe clinical picture.8---10
The incidence of human leukocyte antigen (HLA) A33,
HLA-B35, HLA-B81, HLA-B12, HLA-B51, HLA-DR7, and HLA-
DR5 is greater in patients with RAS than in healthy controls.5
Genetic risk factors also modify a person’s susceptibility
to RAS. These include various DNA polymorphisms through-
out the human genome, especially those associated with the
Immunological
factors Genetic
Local trauma factors
Stress
Vitamin and Recurrent
micronutrient Bacterial
aphthous stomatitis
deficiencies and viral
factors
Drugs Systemic
Hormonal
factors Food allergy
diseases
Figure 1 Factors affecting the pathogenesis of recurrent aph-
thous stomatitis.
J. Sánchez et al.
metabolism of interleukins (IL) (e.g., IL-ß, IL-2, IL-4, IL-5, IL-
6, IL-10, and IL-12), interferon ␥, and tumor necrosis factor
(TNF) ␣.11---20
• Local injury: Local injury is considered a causal agent in
genetically predisposed individuals21,22 and predisposes to
RAS, with early cellular inflammation and edema, as well
as increased viscosity of the extracellular matrix of the
oral submucosa.23 Not all local injuries lead to RAS, since
persons who wear dentures are not at an increased risk.24
Smoking has been reported to act as a protective factor
with respect to RAS.25,26
• Bacterial and viral factors: Various reports have
attempted to establish an association between RAS and
different microorganisms, including bacteria of the genus
Streptococcus, especially Streptococcus sanguinis 2A,27
Helicobacter pylori,28 Lactobacillus,29 and Epstein-Barr
virus.30 However, the results to date have not shown a
clear causal relationship.
• Stress: Stressful life events may trigger new lesions in
predisposed patients. One study concluded that mental
stressors were more associated with RAS than physical
stressors and that stressful life events were more asso-
ciated with the onset of episodes than with the duration
of the episodes.21 Similarly, there have been cases of
diseases, such as Behçet disease, that progress with apht-
hous ulcers and that worsen after considerable emotional
stress.31
• Food allergy: Allergy is thought to be a cause of RAS.
Hypersensitivity to specific substances, oral microorgan-
isms such as S sanguinis, and heat shock proteins have
been proposed as causal factors, although there is no
evidence to date that these are a key cause of the
disease.32,33
• Vitamin and micronutrient deficiencies: Low levels of
iron, folic acid, zinc, and vitamins B1 , B2 , B6 , and B12 have
been reported.34 Sometimes, these deficiencies are asso-
ciated with underlying diseases, such as malabsorption
and gluten enteropathy.
• Immunologic factors: In patients with RAS, the function-
ing of the immune system is modified in response to an
as yet unknown trigger (e.g., bacterial/viral antigens and
stress). Both the innate and acquired immune responses
(humoral and cellular) are altered in patients with RAS.
Many authors believe that the type 1 helper T (TH 1)
response plays the most important role in the develop-
ment of the disease.15,35
• Underlying systemic diseases: RAS appears more fre-
quently in patients with inflammatory bowel disease
(Crohn disease and ulcerative colitis) and in celiac
disease.6,36,37 This association could result from nutri-
tional deficiency, which is a frequent complication of
these diseases. RAS is also more frequent in patients
infected with the human immunodeficiency virus, prob-
ably in association with an abnormal CD4+ /CD8+ ratio and
a reduced neutrophil count.38,39
• Hormonal factors: An association has been reported
between the appearance of aphthous ulcers and the men-
strual cycle. Ulcers are more frequent during the luteal
phase or in the menopause and less frequent during preg-
nancy and in women taking hormonal contraceptives.40
Recurrent aphthous stomatitis 473

Figure 2 Image of minor ulcers on the lip and mucous mem- Figure 3 A, Major ulcers on the mucous membrane of the
brane of the lower lip. lower lip. B, Ulcer on the soft palate.

• Drugs: There are reports of oral aphthous ulcers triggered
by drugs. One case-control study associated an increased
risk of RAS with medication, especially nonsteroidal
antiinflammatory drugs and ß-blockers.42 Nicorandil, cal-
cineurin, and mTOR inhibitors have also been associated
with severe oral ulcers.43---45
the least common type. In this case, there could be up to
100 ulcers that can coalesce, leading to larger ulcers with
irregular borders.
Differential Diagnosis

Table 2 shows the main causes of acute and chronic ulcers

Symptoms
The 3 clinical forms of RAS----major, minor, and
herpetiform----differ in their morphology, distribution,
severity, and prognosis. Table 1 summarizes the main
differences. Despite these differences, all 3 types of RAS
have a significant impact on patients’ quality of life and
interfere with activities of daily living.46 Minor RAS (Fig. 2)
is the most common presentation, affecting 80% of patients.
It progresses without scarring, unlike major RAS (Fig. 3), in
which ulcers take longer to heal and which progresses with
scarring and even residual synechiae. Herpetiform RAS is
in the oral mucosa.
Given the complex differential diagnosis of RAS, a metic-
ulous history must be taken to correctly guide the diagnosis.
Before confirming a diagnosis, we must rule out other clin-
ical pictures in which ulcers are one of the most frequent
signs (Fig. 4).
Diagnosis
Diagnosis of RAS is based on the clinical history and a physical
examination. However, we must always rule out an under-

Table 1 Clinical Classification.

Minor RAS Major RAS Herpetiform RAS

Gender predilection Same in men and women Same in men and women More frequent in women
Size < 10 mm > 10 mm 2-3 mm
Number of ulcers 1-5 1-10 10-100
Morphology Round or oval Round or oval, Small, deep ulcers that
crateriform converge, with irregular
contours
Grayish-white Grayish-white
pseudomembrane pseudomembrane
Erythematous halo Erythematous halo
Localization Nonkeratinized mucosa: Nonkeratinized mucosa: Lips, cheeks, floor of the
lips, cheeks, floor of the lips, soft palate, pharynx mouth, gums
mouth
Healing Ulcers heal in 4-14 d Heal in > 6 wk Heal in < 30 d

Abbreviation: RAS, recurrent aphthous stomatitis.

474 J. Sánchez et al.

Table 2 Differential diagnosis of acute and chronic oral ulcers.

Recurrent aphthous stomatitis

Injury: Braces, necrotizing sialometaplasia
Nutritional deficiency: iron, folic acid, zinc, B1 , B2 , B6 , and B12
Infections
Viral: herpes simplex virus, Coxsackie A, herpes zoster virus, cytomegalovirus, Epstein-Barr, HIV
Bacterial: tuberculosis, syphilis
Fungal: Coccidioides immitis, Cryptococcus neoformans, Blastomyces dermatitidis
Pharmacological: fixed drug eruption, linear IgA dermatosis, drug-induced bullous pemphigoid, erythema multiforme,
Stevens-Johnson syndrome, toxic epidermal necrolysis
Autoimmune diseases: Crohn disease, Behçet disease, celiac disease, systemic lupus erytyematosus, erosive lichen planus,
Wegener granulomatosis
Hematological: anemia, neutropenia, hypereosinophilic syndrome
Fever-associated syndrome: cyclic neutropenia, fever, Sweet syndrome, familial Mediterranean fever,
hyperimmunoglobulinemia D syndrome, and periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA)
syndrome
Blistering diseases: pemphigus vulgaris, linear IgA disease
Hereditary diseases: bullous epidermolysis, chronic granulomatous disease
Other: mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome, IgG4-related disease, tumors, smoking

Source: Scully et al.41 and Suárez-Díaz et al.47 .

shown an association between RAS and positive titers for

antigastric parietal cell antibody, and antithyroglobulin
antibody, and antithyroid microsomal antibody.49
• Microbiological tests: Tzanck smear test or polymerase
chain reaction assay for herpes virus and culture of fungi
and bacteria.
• Skin biopsy: The 3 indications for a skin biopsy are as
follows50 :
a Ulcer of unknown origin that persists for more than 2
weeks with no signs of healing.
b Ulcer of probable origin (after the corresponding diag-
nostic tests) that does not respond after 2 weeks of
appropriate treatment.
c Ulcer brought about by a trigger(s) that does not heal
within 2 weeks of these factors being ruled out.

Punch or incisional biopsy: The specimen must be taken

Figure 4 A, Erythema multiforme major with involvement of
the oral mucosa. B, Geographic tongue. C, Whitish reticular
pattern in oral lichen planus. D, Primary herpes infection.
lying systemic cause when ulcers appear for the first time,
especially in adults.47,48 Fig. 5 shows a diagnostic algorithm
for patients with mouth ulcers.
The recommended additional tests include the following:
• Blood tests: complete blood count, iron, ferritin, folic
acid, zinc, magnesium, and vitamins (B1 , B2 , B6 y
B12 ). Testing should also include transglutaminase and
endomysial antibodies to rule out celiac disease, as well as
antinuclear antibodies. Furthermore, some studies have
from the border of the lesion, including the area of the ulcer
and the perilesional mucosa.
Histopathology study of the ulcers: The histopathol-
ogy image reveals a leukocytic infiltration, which may vary
depending on the duration and severity of the disease. In the
initial phases, which precede formation of the ulcers, we
mainly see an inflammatory infiltrate comprising T lympho-
cytes and monocytes. We can also see isolated mast cells and
plasma cells, which accumulate below the basal layer. More
advanced stages are characterized by a predominance of
polymorphonuclear leukocytes in the center of the ulcer and
mononuclear cells on the periphery.5 Consistent with Poul-
ter and Lehner,51 this type of inflammation is not specific of
RAS and can be seen in other ulcers such as erythema multi-
forme, Behçet disease, lupus erythematosus, and traumatic
ulcers.
Recurrent aphthous stomatitis
Patient with oral aphthous ulcers
Aphthous ulcers on another mucosal surface?
No
Any other systemic symptoms?
No
Order blood and
microbiology workups
Normal
Typical course Indolent course
RAS Biopsy
Figure 5 Diagnostic algorithm for the management of patients with aphthous ulcers. RAS indicates recurrent oral stomatitis.
Treatment
No definitive curative treatment for RAS has been estab-
lished to date. Therefore, the primary objectives of
treatment are to relieve pain, accelerate healing, and
reduce the frequency and severity of episodes of RAS.52
As mentioned above, recurrent ulcers on the oral mucosa
require a correct differential diagnosis. We must also rule
out associated systemic diseases and other treatable causes
before making a diagnosis of RAS and considering treatment.
The approach to therapy should be based on the severity
of symptoms, the frequency and duration of the outbreaks,
the clinical history, and the patient’s ability to tolerate med-
ication. Patients with isolated episodes of simple RAS that
last only a few days require no more than topical treat-
ments for relief of pain and a series of general measures,
mainly good oral hygiene. Systemic therapy is indicated in
patients who experience multiple episodes of RAS and/or
severe cases that involve intense pain and difficulty eating
and do not respond to topical medication.52,53
Despite the frequency of this condition, few high-quality
studies have appropriately evaluated treatment of RAS.
Therefore, there is no standard therapy.52 The multiple top-
ical and systemic treatments used have had varying degrees
of success.
General Measures
Oral hygiene: It is important to ensure appropriate oral
hygiene and to avoid injury, since this leads to mouth
475
Yes
Suspect another condition,
e.g., Behçet disease,
autoinflammatory
Yes diseases, inflammatory
bowel disease, infection
Abnormal
ulcers.31,54 We recommend using a soft toothbrush, tooth-
paste that does not contain sodium lauryl sulfate (grade of
recommendation [GR], A; level of evidence [LE], 1B),55,56
and an alcohol-free mouthwash.31,55,57
Eating: No relevant studies have appropriately addressed
the role of diet in the management of RAS. In general, we
should try to avoid products that are frequently associated
with triggering flare-ups, especially if the patient reports an
association with the products.54,57
Supplements: It is necessary to rule out nutritional defi-
ciencies (e.g., vitamin B12 , folic acid, iron, zinc) in patients
with RAS, since in these cases, patients improve when they
receive appropriate treatment (GR, C; LE, 4). Furthermore,
one study showed that sublingual vitamin B12 at 1000 ␮g/d
for 6 months could reduce the number of flare-ups and
relieve pain in all patients with RAS independently of previ-
ous levels (GR, B; LE, 2B).56---58 Other studies have shown an
improvement with ␻-3 at 1000 mg/d for 6 months (GR, B;
LE, 2B).59 In contrast, supplements with other vitamin com-
plexes in patients without nutritional deficiency have not
led to an improvement in symptoms or a reduction in the
number of lesions (GR, B; LE, 2B).52,57,59,60
Topical Treatments
Topical anesthetics and barrier agents: These agents pro-
vide pain relief. They should be applied several times per
day, preferably half an hour before meals and before teeth
cleaning in order to facilitate their action and at bedtime.
They can be used in combination with other treatments such
476
as topical corticosteroids or amlexanox. The main protective
and anesthetic agents include the following:
• Lidocaine cream 1%, gel 2%, and spray: these are applied
directly on the surface of the ulcers or in the form of
mouthwashes (GR, B; LE, 2A).60
• Benzocaine gel 20%: local anesthetic that relieves pain
and reduces inflammation (GR, B; LE, 2A).61
• Sucralfate suspension: a complex of aluminum hydrox-
ide and sucrose sulfate complex that forms a protective
barrier against ulcers. Several studies recommend mouth
washing with 5 mL for 1-2 minutes 4 times daily (after
teeth cleaning and at bedtime). This substance relieves
pain, speeds up healing, and lengthens the interval
between flare-ups (GR, B; LE, 2A).62,63
Topical antiinflammatory and antiseptic agents: These
help to prevent superinfection by bacteria and fungi and
improve oral hygiene.
• Triclosan 0.15% in ethanol and zinc sulfate: Administered
as 3 mouthwashes per day, this agent reduces the number
of ulcers and the intensity of pain and increases the ulcer-
free interval (GR, A; LE, 1B).63
• Chlorhexidine 0.12%-0.2% in oral solution: 5 mL in rinses
for 1-2 minutes 4 times daily (after teeth cleaning and at
bedtime).60 Some studies report it to be less efficacious
than sucralfate suspension (GR, B; LE, 2B).62
• Diclofenac 3% in hyaluronic acid gel 2.5%: This agent
proved superior to lidocaine in gel for reducing pain after
2-6 hours (GR, B; LE, 2A).60,63
Topical corticosteroids: These are the first-line agents for
RAS60 and can be combined with topical anesthetics, anti-
septics, and barrier agents. They provide pain relief and
reduce the duration and frequency of flare-ups, although
they take several days to exert an effect. They are more
effective if used from the onset of the episode and are
applied several times per day, preferably after teeth clean-
ing and at bedtime. The patient should be advised not to
eat at least during the following half hour.62,64 The available
options are as follows:
• Triamcinolone acetonide 0.1% in Orabase: This is applied
on the lesions 3-4 times per day. It has proven to be a safe
and effective treatment (GR, B; LE, 2B).60
• Dexamethasone solution (0.5 mg/5 cc) or ointment: Rins-
ing every 5 minutes, 3-4 times per day or applying the
ointment on the ulcers 3 times per day has proven to be
effective and safe (GR, A; LE, 1B).59,64
• Clobetasol 0.05% in gel, ointment, or Orabase: The agent
is applied to the lesions 2-3 times per day. As this is the
most potent corticosteroid, it is reserved for the most
severe cases.60
Amlexanox 5%: Topical inflammatory agent that, when
applied on the lesions in the form of a 5% paste 4 times per
day (after meals and at bedtime) has proven to be effective
for the management of pain and for speeding up healing in
several studies (GR, B; LE, 2B).52,56,61,65 Amlexanox 5% is one
J. Sánchez et al.
of the most cost-effective topical treatments, together with
triamcinolone acetonide.61
Cauterization: Applied with hydrogen peroxide 0.5% solu-
tion or silver nitrate 1%-2%, this approach reduces pain and
speeds up healing (GR, B; LE, 2B).56,57
Other topical treatments: Many other topical treatments
have been used, including tetracyclines in mouthwash,
doxycycline in denture adhesive, nicotine gum, liquid
diphenhydramine mouthwash, or camel thorn distillate,
most of which have been reported in poor-quality studies,
with disparate results and no evidence to recommend their
use.52,57,66,67
Systemic Treatments
Patients who experience severe and/or frequent episodes
of RAS that are refractory to general care and to topical
treatments (see above) should consider adding a systemic
treatment. This is selected based on the severity of symp-
toms, comorbid conditions, and the patient’s tolerance and
preferences.
First-Line
Oral corticosteroids: Oral corticosteroids have been used
effectively in long regimens at lower doses, for example,
oral prednisone at 5 mg/d for 3 months (GR, B; LE, 2A),67
and in shorter regimens, with doses of 20 to 40 mg/d for 4-7
days, with subsequent gradual reduction of the dose. This
leads to relief of pain, faster healing, and a reduction in the
number of episodes (GR, B; LE, 2A).52,54,56,57
Second-Line
Alternative systemic agents should be considered in patients
who do not respond to intermittent therapy with sys-
temic corticosteroids, patients who require frequent or
longer courses of corticosteroids, and patients who can-
not undergo treatment with corticosteroids for other
reasons.
Colchicine: Colchicine is an antimitotic drug with specific
immunomodulatory and antifibrotic effects. It has been used
at 0.5 to 2 mg/d, with various results.52,56,57 In some publi-
cations, it is considered a systemic drug of choice at doses
of 1-2 mg/d over long periods, depending on the severity of
symptoms and tolerance.56,57,68 In contrast, after an analysis
of published studies, the 2012 Cochrane review52 concluded
that this drug was not useful in comparison with oral corti-
costeroids for the treatment of RAS, since its efficacy rates
are equal to or lower than those of corticosteroids, although
it has a greater rate of adverse effects (mainly affecting the
gastrointestinal tract) (GR, B; LE, 2A).52,69,70
Thalidomide: Thalidomide has been used at 50 to
100 mg/d for several months with good results.56,57,70 A
study performed in Brazil showed it to be more effec-
tive and better tolerated than dapsone, colchicine, and
pentoxyphillin.71 We must remember that this drug is terato-
genic and can cause sleepiness, paresthesia, and irreversible
peripheral neuropathy. Therefore, patients should be care-
Recurrent aphthous stomatitis
fully selected and informed. It is also advisable to take a
history and perform an examination at all follow-up visits
to rule out signs of peripheral neuropathy. If this condi-
tion is suspected, treatment should be discontinued and an
electromyogram ordered (GR, B; LE, 2B).56,57,70
Dapsone: Dapsone reduces the number and size of the
ulcers.63 It is usually started at 25-50 mg/d, increasing to a
maximum of 150 mg/d depending on the response and on
tolerance. Glucose-6-phosphate dehydrogenase should be
determined before starting therapy with dapsone (GR, B;
LE, 2A).60,67
Montelukast: Montelukast is a leukotriene inhibitor
that, in some trials, has been shown to improve pain
and accelerate healing of mouth ulcers, as well as
reduce the appearance of new lesions with a dose
of 10 mg/d for 1 month, followed by 10 mg every 2
days for a further month.72 Montelukast is less effica-
cious than prednisone, although it has fewer adverse
effects and is very well tolerated. Therefore, it could
prove to be a good option for long-term treatment
(GR, B; LE, 2B).52,56,72
Clofazimine: Clofazimine is an antimicrobial agent
that has been used at 100 mg/d for 30 days followed
by 100 mg every other day for 6 months. In a study
with a high risk of bias, it improved symptoms and
reduced the number of flare-ups compared with colchicine
(GR, B; LE, 2B).52,69
ß-Glucans: ß-Glucans comprise a group of polysac-
charides found in some bacteria, plants, and fungi.
They have been used at doses of 10 mg of 1,3-1,6 ß-
glucan twice daily, with an improvement in the severity
of the ulcer compared with placebo.52,73 Evidence in
favor of or against this approach in RAS is insufficient
(GR, B; LE, 2B).52
Pentoxifylline: This nonselective phosphodiesterase
inhibitor with hemorheological properties specifically
inhibits production of TNF-alfa and possibly production of
some other type 1 helper T cells and proinflammatory
cytokines such as IL-1ß, which are thought to play an impor-
tant role in the development of RAS. Pentoxifylline has
been used at 400 mg/8 h, with improvement of the lesions,
although these recur when the drug is discontinued. Evi-
dence in favor or against its use is insufficient (GR, B; LE,
2A).52,63
Levamisole: Levamisole is an anthelmintic and
immunomodulatory agent.60 Results from trials with
doses of 50 mg/8 h for 3 to 11 days per flare-up for at least 6
months show disparate efficacy outcomes, with insufficient
evidence in favor of or against its use (GR, B; LE, 2A).52,62
Doxycycline: Doxycycline at 20 mg/12 h revealed no dif-
ferences with respect to placebo in a study with a high risk
of bias (GR, B; LE, 2A).52
Biological Treatments
Anti-TNF-alfa: Data from case series show that anti-TNF
alfa agents (etanercept, adalimumab, infliximab, and goli-
mumab) have been used successfully for treatment of severe
and recalcitrant RAS.62,74 This seems to be a specific class
477
effect, with no significant differences between the anti-TNF
agents used. Furthermore, it seems that failure with any of
these drugs does not imply the lack of a response to other
anti-TNF agents (GR, C; LE, 4).62,74 These drugs should be
chosen based on disease severity, efficacy, potential adverse
effects, and costs.
Other Treatments
CO2 , Nd:YAG, and diode laser: Some studies showed that
laser therapy had similar or superior efficacy to topical
corticosteroids,67 with immediate relief of pain and accel-
erated healing of the ulcers (GR, B; LE, 2A).53,57,75
Apremilast: Apremilast is an oral phosphodiesterase-4
inhibitor. In one published case of major RAS that was refrac-
tory to multiple topical and systemic treatments, 6 weeks’
treatment with apremilast (loading dose of 10 mg/d increas-
ing progressively to 30 mg/12 h) led to complete resolution
of the lesions, with no recurrences after 1 year of treatment
(GR, C; LE, 4).76
Bee propolis: This resinous material is produced by bees
and is obtained from the buds of poplars and conifers.
One study with a high risk of bias showed that a daily
capsule of 500 mg taken over 6 months led to a reduc-
tion in the number of outbreaks. However, evidence was
insufficient to recommend or not recommend its use
(GR, B; LE, 2A).52,77
Homeopathy: One study with a high risk of bias con-
cluded that homeopathy could improve pain and accelerate
the cure of ulcers, without there being sufficient evidence
for recommending or not recommending its use (GR, B; LE,
2A).52,78
Traditional Chinese medicine: Some traditional thera-
pies have been used for hundreds of years. A recent review
tried to evaluate the scientific aspects of this approach by
evaluating several of the treatments used, such as Liuwei
Dihuang pills (composed of Cornus officinalis, Rehman-
nia glutinosa, Rhizoma dioscoreae, Cortex moutan radicis,
Poria cocos, and Alisma plantago-aquatica), bergamot, Qing
Wei powder, and Yiqing capsules. The authors concluded
that some treatments in traditional Chinese medicine may
be effective and safe for the treatment of RAS, although
high-quality studies would be necessary to confirm these
findings. Evidence to recommend their use is insufficient
(GR, B; LE, 2B).79
Several publications address the drugs used in the treat-
ment of oral aphthous ulcers that manifest in systemic
diseases, such as Behçet disease, but not in RAS per
se. These include azathioprine, methotrexate, ciclosporin,
and interferon-alfa. Given that neither their efficacy
with respect to the etiology and pathogenesis of apht-
hous ulcers nor their role in RAS has been studied, we
decided not to include these drugs in order to avoid
confusion.80---83
Conflicts of interest
The authors declare that they have no conflicts of interest.
478 J. Sánchez et al.

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